Human immunodeficiency virus-1 (HIV) In chronic HIV infection, ongoing HIV replication leads to gradual destruction of the immune system and acquired immunodeficiency syndrome (AIDS). The amount of HIV circulating in serum or plasma (viral load) reflects HIV replication throughout the lymphoid system and is a strong predictor of disease progression. The Viral Epidemiology Branch's cohort studies of HIV-infected hemophilia patients and homosexual men provide a valuable resource for studying predictors of HIV disease progression. An area of active research is the use of statistical methods to model the complex relationship between markers, such as HIV viral load, and disease progression, to better understand pathogenesis. We have examined the relationship between HIV viral load and disease progression in persons with late-stage HIV infection. We studied 389 HIV-infected subjects from the Multicenter Hemophilia Cohort Study who had CD4 counts below 200 cells/mm3. For these persons with advanced infection, HIV viral load was a strong predictor of AIDS risk. Interestingly, this effect was most pronounced immediately after the HIV viral load was measured, and it attenuated over time, implying that viral load reflects short term risk and thus, implicitly, immune deficiency. Indeed, viral load remained predictive of short term risk even after controlling for CD4 count, an established measure of immune function. These findings have implications for the clinical management of HIV-infected patients, for whom decisions regarding prophylaxis, treatment, and diagnostic evaluation often involve assessment of immune status. HIV and cancer We are currently using the AIDS Cancer Match Registry study, which links data in U.S. AIDS and cancer registries, to study factors associated with cancer risk in HIV-infected persons. This study includes over 300,000 subjects with AIDS. Using data from this study, we have described the overall spectrum of cancer in HIV-infected individuals. We have also studied cancers in informative subgroups with HIV infection (e.g., elderly adults) and the occurrence of rare cancers (e.g., Merkel cell carcinoma). Hepatitis C virus infection is common in some groups of HIV-infected persons, such as intravenous drug users and hemophiliacs. We have examined the relationship between hepatitis C virus and hepatocellular carcinoma by comparing the risk for this cancer in various HIV risk groups. Risk for hepatocellular carcinoma was highest in groups with high hepatitis C virus prevalence, suggesting that this virus causes cancer among persons with AIDS. Notably, however, even in groups with low hepatitis C virus prevalence, hepatocellular carcinoma risk was higher than in the general population. Human herpesvirus 8 (HHV-8) Human herpesvirus 8 (HHV-8), the viral cause of KS, may play an etiologic role in some subtypes of NHL. We were led to this conclusion through analysis of AIDS Cancer Match Registry data. We found that persons with AIDS?associated KS had higher risk for immunoblastic lymphoma than did others with AIDS. This relationship was specific, since no association was found between KS and other NHL subtypes or other cancers. Subsequently, in a laboratory-based study of NHLs from individuals with AIDS-associated KS, we documented KSHV in 43% of immunoblastic lymphomas, compared with 0% in other NHLs. We are planning additional studies to confirm this link between HHV-8 and immunoblastic lymphoma. HHV-8 infection is necessary but not sufficient for development of KS, even among person with HIV co-infection. Using data from the District of Columbia Gay cohort study of homosexual men, we are presently examining laboratory measures of immunity and HHV-8 infection to identify predictors of AIDS-associated KS. Another area of research is the epidemiology of HHV-8. For this purpose, our group has developed enzyme immunoassays to detect HHV-8 antibodies and evaluated these assays using a variety of analytic approaches. Most recently, we have completed fieldwork for a study of HHV-8 infection in Ugandan children with sickle cell anemia. This study will allow us to examine risk factors for HHV-8 infection in African children, particularly blood transfusions, socioeconomic status, and mothers' infection status.